delta 4, 6(14)-19-norandrostene derivatives



United Sates Pate A -19-NORANDROSTENE DERIVATIVES Eugene J. Agnello and Gerald D. Laubach, Jackson Heights, N. Y., assignors to Chas. Pfizer & 'Co., Inc., New York, N. Y., a corporation of Delaware No Drawing. Application September 4, 1958 Serial No. 758,916

7 Claims. (Cl. 260-23955) CH3 CH3 Ii] J and the A -dehydro derivatives thereof wherein Z is selected from the group consisting of These other com- 2 R is selectedfrom the group consisting of hydrogen and acyl hydrocarbon containing up to ten carbon atoms and Alk is selected from the group consisting of alkyl groups containing up to three carbon atoms.

Suitable compounds for the preparation of the valuable compounds of this invention include those represented by the formula CH3 I10 I wherein Z has the same meaning as above. pounds can be prepared from the known compound A -19- norandrostene-l lB-hydroxy-3,17-dione in accordance with the procedure fully described and illustrated in copending and concurrently filed patent application Serial No. 758,914. This application describes the preparation of these compounds from the corresponding 95,11fi-oxido- 8(14)-dihydronorandrostene derivatives by treatment with perchloric acid. The reaction is carried out in an alcohol-free hydrocarbon or halogenated hydrocarbon These comsolvent such as petroleum ether, benzene, chlorobenzene,

toluene, ethylene dichloride, chloroform or carbon tetra chloride at a temperature of from about 0 C. to about 10 C. during a period of from about 2 to about 25 minutes using at least an equivalent quantity of 60% per chloric acid. An excess of perchloric acid as high as 200% can be used to ensure complete reaction.

The desired product is isolated by diluting the reaction mixture with from 1 to 3 times its volume of ice cold water. The resulting aqueous mixture is extracted with a suitable solvent, for example, chloroform or a mixture of chloroform in ethyl acetate. The organic solution is dried over an anhydrous drying agent such as sodium or magnesium sulfate, the drying agent removed and the desired product isolated by evaporation of the solvent, preferably in vacuo. It may be purified by trituration with a 1:1 mixture of ethyl acetate in ether followed by recrystallization from ethyl acetate.

The A -compounds of this invention are prepared by dehydration of the above illustrated llfi-hydroxyl compound with, for example, p-toluenesulfonic acid in refluxing benzene or preferably with methyl sulfonyl chloride in pyridine. In the preferredmethod, the starting compound is allowed to stand together with an excess of methyl sulfonyl chloride in pyridine at a low temperature, for example, 5 to +5 C. for a period of from about 16 to about 30 hours. The intermediate mesylate compound can be isolated or alternatively the reaction mixture can be refluxed preferably in an inert atmosphere such as nitrogen for a period of from about 1 to about 4 hours. The desired compound is isolated by evaporating the solvent in vacuo.

The M -compound of this invention is converted to a 95,11fi-oxide of this invention using the procedure of Fried and Sabo as described in the Journalof the American Chemical Society, vol. 79, page 1130. The compound is first converted to a bromohydrin using N-bromoacetarnide and perchloric acid in peroxide-free dioxane. The bromohydrin, that is, the 9a-bromo-115-hydrox'yl compound is converted to a 9,8,11fi-oxide using an alkaline reagent such as potassium acetate.

In-this procedure, the bromohydrin is refluxed for a period of from about 30 minutes to about 1 hour in 'a dioxane-absolute alcohol solution containing from about 500% to about 800% excess by weight of anhydrous potassium acetate. At the end of the reaction period the desired product is precipitated by the addition of water and isolated by filtration. It is often possible to obtain increased yields of product by concentrating the filtrate and isolating successive groups of productby filtration. The procedure is fully illustrated in the appended examples. v

The above-described bromohydrin is claimed in copending and concurrently filed patent application Serial No. 758,918.

The A -dehydro compound of this invention can be prepared from the above described compounds by application of the reactions set forth in earlier filed patent applications Serial No. 526,554 filed August 4, 1955, and Serial No. 633,538, filed January 10, 1957. These applications described the method for the introduction of double bonds at the 6(7)-position by dehydrogenation of a 3-keto-6-dihydro-A -steroid compound with a quinone having an oxidation-reduction potential less than -0.5 at a temperature of between C. and C. in an inert organic solvent having a boiling. point of at least about 70 C. These solvents include mono-nuclear aromatic hydrocarbons, mono-nuclear halogenated aromatic hydrocarbon solvents, oxygenated polar alicyclic organic solvents and oxygenated polaraliphatic organic o solvents, Typical solvents include tertiary butanol,

n-amyl alcohol, hexanol, isoamyl alcohol, heptanol- 3, cyclohexanol, ortho-dichlorobenzene, xylene, tertiary amyl alcohol, secondary aruyl alcohol, benzene, toluene, acetic acid, propionic acid, butyric acid, butyl acetate, amyl acetate, hexyl acetate, butyl propionate, propyl propionate and amyl propionate. The preparation of the valuable compounds of the instant invention using the process described in the earlier filed applications is more fully illustrated in the appended examples.

Various modifications at the C position can be made by procedures well. known in the art. For conversion of the 17-li6l0 group to a l7-hydroxyl group the B-keto group is preferentially converted to a pyrroliclinyl derivative, the l7-keto group is then reduced with lithium aluminum hydride and the pyrrolidinyl group removed by refluxing in a sodium acetate-acetic acid buffered aqueous-methanol solution. This reaction is described in detail by Heyl and Herr in the Journal of the American Chemical Society, 75, page 1918 (1953). The vinyl group can be introduced at the C position by treating the l7-keto with acetylene in the presence of a potassium tert-alkoxide (for example, potassium tert-amyl alkoxide) and reducing the thus produced ethynyl group by catalytic hydrogenation. For the introduction of the vinyl group the 3-li6i0 group should again be protected by a pyrrolidinyl group which is, of course, sub sequently removed. The 17-keto group can be converted to a tertiary alcohol, that is, an alkyl and hydroxyl group can be introduced at the l7-position by treatment with an organo-metallic compound of the type RLi or RMgX wherein R is alkyl up to four and X is a halogen. For the introduction of the vinyl group or the reaction with an organo-metallic compound the 3-keto group should be protected by a pyrrolidinyl group as described above. A l7-hydroxyl group can be readily esterified with the usual esterifying agents if it is the hydroxyl group of a secondary alcohol. If it is the hydroxyl of a tertiary alcohol it can be esterified by refluxing in a liquid anhydride, for example, acetic or propionic anhydride or in the case of a solid anhydride by heating the compound at about 100 C. in a hydrocarbon solvent solution such as xylene containing the anhydride and catalytic amounts of potassium acetate. Esters and acid esters of the 17- hydroxyl group can be obtained in this manner. An llfi-hydroxyl group can be converted to a keto group by oxidation, for example, with chromic acid. If, however, there is a secondary hydroxyl group at the 17- position, it is best to acylate this group before oxidizing the group at the ll-position. As stated above, all of these reactions are conventional in the art.

Although the reactions described above are applicable to compounds in which the l7-position carries a free fi-hyrdoxyl group, for optimum results it is best that this hydroxyl group be acylated with an acyl hydrocarbon group containing up to ten carbon atoms. The term acyl hydrocarbon includes acyl hydrocarbon groups containing only carbon, hydrogen and oxygen derived from monocarboxylic or dicarboxylic acids. In the event that the acyl hydrocarbon group is one derived from a dicarboxylic acid, it is often advantageous to treat the isolated therapeutically active compound with a base derived from an alkali metal or alkaline earth metal to prepare a metal salt. These bases include, for example, sodium, potassium, barium and calcium hydroxide as well as the corresponding carbonates and bicarbonates. Products so prepared are especially useful because of their increased solubility in water.

The following examples are given solely for the purpose of illustration and are not to be construed as limitations of this invention, many apparent variations of which are possible without departing from the spirit or scope thereof.

EXAMPLE I A (199(19-1 9-norandr0statriene-3,17-dione A solution containing 3 ml. of pyridine and 0.59 ml. of methylsulfonylchloride, together with 240 mg. of

4 A -l9-norandrostadiene-11fi-ol-3,17-dione was maintained at a temperature of 0 C. for 24 hours. At the end of this period a small 'amount of ice and water was added and the resulting mixture extracted with methyl acetate. The organic layer was separated and washed successively with equal volumes of Water, 2 N hydrochloric acid and again with water. It was concentrated to dryness to leave the llfi-mesylate as a residue. The residue was dissolved in 3 ml. of pyridine and the solution refluxed in a nitrogen atomsphere for 2 hours. The resulting solution Was extracted with ethyl acetate, the organic layer washed as described above .and the desired product isolated by concentrating to dryness.

A -lQ-norandrostatriene-17/8-ol-3-one 17-acetate A -l9-norandrostatetraene-17,3 ol 3 one 17- acetate l7ot methyl-A -l9-norandrostatriene 17,8 ol 3- one 17-acetate 17a-methyl-A 19 norandrostatetraene 17,6

ol-3-one 17-acetate 17u-ethyl-A -l9-norandrostatriene-1718-01- 3 one 17-acetate l7u-ethyl-A -19 norandrostatetraene 17B ol- 3-one l7-acetate 17a-propyl-A -19-norandrostatriene 17B 01-3- one 17-acetate 17a-propyl-A -l9-norandrostatetraene 17,8 ol- 3-one 17-acetate 17u-ethynyl-A -19-norandrostatriene 17B ol- 3- one 17-acetate 17u-ethyny1-A -l9 norandrostatetraene 17pol-3-one l7-acetate 17u-vinyl-A -l9 norandrostatriene 17p ol 3- one l7-acetate 17ot-vinyl-A -19 norandrostatetraene 17,3 ol- 3-one 17-acetate The above compounds were each prepared using the foregoing precedure.

EXAMPLE II Qa-bronw A -19-n0randrostadiene-1 Idol-3,1 7-di0ne To a suspension of A -19-norandrostatriene- 3,17-dione, prepared as described in the above example, (2.4 g.) in pure peroxide free dioxane (20 ml.) and 3.65 ml. of 0.46 N perchloric acid added in the dark at room temperature with stirring for a one hour period 1.14 g. of N-bromoacetamide. At the end of two hours all of the starting material had dissolved and 2.5 ml. of sodium sulfite solution was added with stirring. A few grams of ice in 20 ml. of chloroform was added and the layers separated. The organic layer was Washed twice with water while maintaining the temperature at about 20 C. by the occasional addition of ice. The organic solution was concentrated in vacuo and triturated in acetone. The mixture was maintained at a temperature of about 5 C. and the desired product recovered by filtration.

Using this procedure each of the compounds in the list given with Example I were converted to the corresponding 9a-bromo-ll 8-hydroxy steroids.

EXAMPLE III 9/5,] 1 fi-oxido-M -19-n0randr0stadiene-3J 7-dione A solution of 2.3 g. of the compound prepared in the previous example in 75 ml. of dioxane was added to a solution of 15.8 g. of anhydrous potassium acetate in ml. of absolute alcohol at a temperature just below the reflux temperature of the alcohol solution. The mixture was brought to reflux within three minutes and the reaction allowed to proceed for a total of forty minutes. After cooling in an ice bath 400 ml. of ice water was added with stirring and the desired product precipitated.

913,1lfi-oxido-A -19-norandrostatriene 17p o1 3- one 17-acetate 95,11fl-oxidodl -19-norandrostatriene 17,6 ol 3- 'one 17-acetate 9,8,1 1 ,B-oxido-A -l9-norandrostatriene-3, l7-dione 913,1lB-oxido-l7a-methyl-A 19 norandrostadiene- 17fl-ol-3-one 17-acetate 9,9,1lfi-oxido-17u-methyl-A 19 norandrostatriene- 17fl-o1-3-one 17-acetate 95,1lfl-oxido-17a-ethyl-A -19-norandrostadiene 17$- ol-3-one 17-acetate 9fl,llfi-oxido-l7a-ethyl M5304) 19 norandrostatriene- 17 8-ol-3-one 17-acetate 9fl,ll}8-oxido-17u-propyl A 19 norandrostadienel7fl-ol-3-one l7-acetate 95,1IB-oxido-17a-propyl-A 19 norandrostatriene- 17fl-ol-3-one 17-acetate 95,1lfl-oxido-l7a-ethynyl-A 19 norandrostadienel75-ol-3-one 17-acetate 95,11fi-oxido-l7a-ethynyl-A -19 norandrostatriene- 17B-ol-3-one l7-acetate 96,11/3-oxido-17a vinyl A 19 norandrostadiene- 17B-ol-3-one 17-acetate 9,8,11fl-oxido-lh-vinyl M16504) 19 norandrostatriene- 175-ol-3-one 17-acetate EXAMPLE IV The 17-acetates prepared as described above are all converted to free alcohols by alkaline hydrolysis using conventional procedures.

EXAMPLE V A variety of 17-esters of the free alcohols prepared as described in the previous examples were each prepared by acylation using conventional methods. The compounds prepared include formates, propanoates, propenoates, isobutyrates, hexanoates, benzonoates, octanoates, decanoates, hemisuccinates, trimethyl acetates, cyclopentylpropionates, etc. The acid esters of dicarboxylic acids such as the hemisuccinate have the advantage that alkali metal salts and alkaline earth metal salts can be prepared from them by treatment with molar proportions of a base such as sodium or potassium bicarbonate or barium hydroxide. These salts are water soluble, an advantage not possessed by the free alcohols themselves or by ordinary esters thereof.

What is claimed is:

1. A compound selected from the group consisting of those having the formulas CH; CH; I U 9U and the A -dehydro derivatives thereof wherein Z is selected from the group consisting of 7. 95,1118 oxido-A -19-norandrostatriene-17fl-ol- 3-one-l7-acetate.

No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULAS 